Hypoxia-inducible factor activators: a novel class of oral drugs for the treatment of anemia of chronic kidney disease

Anemia is a hallmark of chronic kidney disease (CKD), worsens with disease progression, and profoundly affects a patient's well-being. Major pathogenic factors are inadequate kidney erythropoietin (EPO) production and absolute and functional iron deficiency. The 2 mainstays of current anemia treatment are a) replacement therapy with recombinant EPO or 1 of its glycosylated derivatives, administered subcutaneously or intravenously, and b) intravenous (IV) iron injections. Over the past 5 years, hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitors (HIF-PHIs) have been approved in many countries for the management of anemia in both nondialysis and dialysis-dependent patients with CKD. Due to cardiovascular safety concerns, only 2 HIF-PHIs, daprodustat and vadadustat, have been approved for marketing in the United States, and only for patients on maintenance dialysis. HIF-PHIs are oral agents that are effective at improving and maintaining hemoglobin levels by activating HIF signaling in anemic patients with CKD. They stimulate the production of endogenous EPO, increase total iron-binding capacity through their direct effects on transferrin gene transcription, lower plasma hepcidin indirectly, and have beneficial effects on red blood cell parameters. Here, we discuss the mechanisms of action and pharmacologic properties of different HIF-PHIs. We discuss unwanted on-target and off-target effects, review cardiovascular and other safety concerns, and provide a benefit/risk-based perspective on how this new class of oral drugs might impact current anemia management in CKD. A clinical case is presented that highlights the clinical complexities and therapeutic challenges in managing anemia in CKD.